GATA2 haploinsufficiency causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasi

Abstract

The transcription factor GATA2 has pivotal roles in hematopoiesis. Germline GATA2 mutations result in GATA2 haploinsufficiency characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical symptoms in GATA2 patients are diverse and mechanisms driving GATA2 related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on hematopoiesis, we generated a zebrafish model carrying a heterozygous mutation in gata2b, an orthologue of GATA2. Morphological analysis revealed progression of myeloid and erythroid dysplasia in gata2b+/- kidney marrow (KM). Single cell RNA sequencing on KM cells showed that the erythroid dysplasia in gata2b+/- zebrafish was preceded by a differentiation block in erythroid progenitors, hallmarked by downregulation of cytoskeletal transcripts, aberrant proliferative signatures and ribosome biogenesis. Additionally, transcriptional and functional analysis of Gata2b haploinsufficient hematopoietic stem cells (HSCs) indicated that proliferative stress within the HSC compartment possibly contributes to the development of myeloid and erythroid dysplasia in gata2b+/- zebrafish.

The role of GATA2 in adult hematopoiesis and cell fate determination

“…The precise expression regulation of GATA2 has a profound impact on hematopoietic development, as high expression of GATA2 is required for HSC self-renewal and maintenance, while procedural downregulation is imperative to facilitate downstream lineage differentiation. Recent advances in the field in terms of new animal models to understand the precise role of GATA2 in lineage differentiation can significantly contribute to the development of treatments for the life-threatening cytopenias from which the majority of GATA2 deficiency syndrome patients suffer ( Gioacchino, et al, 2021a ; Gioacchino et al, 2021b ; Mahony et al, 2023 ). In recent years, the employment of single cell sequencing technologies resulted in remarkable progress in the comprehension of the molecular regulatory processes governing hematopoietic cell fate determination ( Ranzoni et al, 2021 ; Zeller et al, 2023 ; Zhang et al, 2023 ).…”

“…This could point to a defect in correct downregulation of GATA2 in GATA2 deficiency patients. In a zebrafish model for Gata2 deficiency, such a mechanism was observed, where heterozygous loss of Gata2b (orthologue of GATA2) resulted in dysplastic erythroid lineage cells caused by excess of open chromatin at the Gata2b locus ( Gioacchino et al, 2021b ).…”

“…But if and how this influences the CD4/CD8 ratio is unclear. B cell lineage differentiation defects were observed in a zebrafish model for GATA2 deficiency syndrome after deletion of Gata2b ( Avagyan et al, 2021 ; Gioacchino et al, 2021b ). Gata2b deficiency resulted in increased lymphoid differentiation, but incomplete B cell differentiation due to a loss of B cell lineage transcription factor accessibility.…”

“…Therefore, there will always be a need for model systems to study human disease. Current zebrafish and mouse models of GATA2 deficiency syndrome were only able to partially phenocopy the lineage differentiation defects observed in patients ( Dobrzycki et al, 2020 ; Abdelfattah et al, 2021 ; Gioacchino et al, 2021a ; Avagyan et al, 2021 ; Gioacchino et al, 2021b ; You et al, 2022 ; Mahony et al, 2023 ). This could be due to significant disparities between animal models and humans concerning adult size, aging and niche components.…”